This IPCP-HTM application made in response to RFA Al-oy-ooi contains three Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD and co-Principal Investigator, Robin A. Shattock, PhD. The purpose of the program is to conduct in vitro and in vivo pre-clinical and animal model-based research intended to facilitate the development of a vaginal microbicide based on the use of inhibitors of HIV-i entry, applied alone and/or in combination. Our goal is to use our collective knowledge of virology, immunology, formulation chemistry and mammalian biology to help develop a mechanism-based, HIV-i-specific microbicide(s). An emphasis will be the development and evaluation of long-lasting microbicide formulations and delivery methods, such as controlled release vaginal rings that can provide a continuous and constant supply of active compounds in situ for a period of weeks/months after the application of a single device, and semi-solid formulations that could be applied once-daily or even less frequently. The inhibitors that we will study include, but may not be limited to: the small molecule CCRs inhibitor, CMPDi67 (Merck);the small molecule attachment inhibitor BMS-C (Bristol-Myers Squibb);the small molecule CXCR4 inhibitor AMD3465 (AnorMED);the gp4i-based peptide fusion inhibitor, T-1249 (Trimeris). We propose: Research Project I: Robin Shattock, Characterization of entry inhibitors in human cervical and rectal tissue models, and in dendritic cells; Research Project II: Karl Malcolm, Practical Formulations of HIV-i Entry Inhibitors;Research Project III: Ronald Veazey, Testing practical microbicides in macaques;Virology and Immunology Core: John P. Moore;Administrative Core: John P. Moore. Other senior members of the team include Melissa Robbiani and Mark Mitchnick (Particle Sciences, Inc) who will participate in Research Projects I and III, respectively, under Cooperative Agreements, and Steven Wolinsky who will take part in the Virology and Immunology Core, also under a Cooperative Agreement. The involvement of Particle Sciences fulfills the mandated corporate element of the proposed research program. If this application is successfully peerreviewed and approved for support by the NIH, the International Partnership for Microbicides will provide the majority of the funding required to support the research programs headed by Drs. Shattock, Robbiani and Wolinsky, as outlined in the Program Overview section of the application.